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The Serenity Role Playing Game book is a complete game in and of itself. It's the "core rules" for the Serenity game.
You don't need the Cortex System book, and in fact, due to differences between the two, it's only going to confuse things.
You probably should get the Big Damn Heroes Handbook. The rules and setting expansion it provides is worth the money. ...

There are two forms of Target Number rolled against in the Serenity RPG:
Fixed Difficulty values (p. 141) set by rules and/or the GM.
Note that p. 141 lists 8 labeled difficulties with fixed TN's.
Opposed Rolls (p. 143) Someone else's skill roll is the TN.
Most combat rolls are opposed; your TN is a roll by the opponent. If the opponent can't, won't or ...

Good timing: we just walked through rule changes.
I believe one of the big changes deals with experience points. The original Serenity rules had a (IMHO) stupid transition point between Plot Points and Advancement Points (if you held onto more than six plot points, you converted the extra to Advancement Points). The new rules scrapped it and just has two ...

I played a lot of the classic TSR space opera game Star Frontiers back in the day, and the many published adventures for it could easily be adapted to Serenity. And, you're in luck, TSR allowed all the Star Frontiers stuff to be published for free on the Web! (registration required)
The Alpha Dawn adventures tend to not involve the PCs having actual ...

Traveller would be ideal for this. If you can get 101 cargoes, 101 travellers, and 101 plots, 101 XXX then you are a winner. They are awesome sources books. "What do you mean they are LIVE animals? I thought the cargo manifest says "dead". It does, look. You don't care. Well, that's just grand..."
The old ICE Spacemaster game world had a very similar ...

Cortex's combat system is an "attack roll, dodge roll" system, not an "attack roll against an armour defense class" system. Almost all combat rolls are to resolve Opposed Actions (Serenity RPG, p. 143), which means you're going to be rolling to beat the dice result of the opponent. Weapons change what you roll to determine damage. Armour absorbs a number of ...

This is a bit hard of a question to answer, since you included Leverage in the tags, which includes Cortex Plus as a result. Both Smallville and Leverage use Cortex Plus as a base, which isn't really the same system, but more of a design language that influences the design of a specific system.
The previous Cortex systems are something like Savage Worlds, ...

Big Damn Heroes Handbook is, functionally, a supplement. It can't stand alone as a ruleset.
It alters the advantages and disadvantages to be more like standard Cortex System, and expands the list. It provides options for tweaking the skill system. It provides some extra material on relationships, as well, giving them mechanical teeth.
Most of it is ...

I would recommend the MechWarrior/Battletech RPGs, and do some scaling back on the universe (IE no battlemechs, and limit factions to Davion, Marik, and Capellan) since it has the high tech/futuristic thing going for it, and Mechwarrior 3e has a pretty good ruleset involving a lifepath that you can easily adapt to the Unification War.